A positive feedback Loop between glial cells missing 1 and human chorionic gonadotropin (hCG) regulates placental hcGβ expression and cell differentiation

Mei Leng Cheong, Liang Jie Wang, Pei Yun Chuang, Ching Wen Chang, Yun Shien Lee, Hsiao Fan Lo, Ming Song Tsai, Hungwen Chen*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

18 Scopus citations

Abstract

Human chorionic gonadotropin (hCG) is composed of a common α subunit and a placenta-specific β subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cyclic AMP (cAMP). Although the ubiquitous activating protein 2 (AP2) transcription factors TFAP2A and TFAP2C may regulate hCGβ expression, it remains unclear how cAMP stimulates placenta-specific hCGβ gene expression and trophoblastic differentiation. Here we demonstrated that the placental transcription factor glial cells missing 1 (GCM1) binds to a highly conserved promoter region in all six hCGβ paralogues by chromatin immunoprecipitation-on-chip (ChIP-chip) analyses. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate the hCGβ promoter through a GCM1-binding site (GBS1), which also constitutes a previously identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between the hCGβ promoter and GCM1 but not TFAP2C. Indeed, the hCG-cAMP- protein kinase A (PKA) signaling pathway also stimulates Ser269 and Ser275 phosphorylation of GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the fusogenic protein syncytin-1, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCGβ expression and cell differentiation.

Original languageEnglish
Pages (from-to)197-209
Number of pages13
JournalMolecular and Cellular Biology
Volume36
Issue number1
DOIs
StatePublished - 2016
Externally publishedYes

Bibliographical note

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© 2015, American Society for Microbiology. All Rights Reserved.

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